Reversing myeloid-derived suppressor cells mediated immunosuppression via p38α inhibition enhances immunotherapy efficacy in triple negative breast cancer
Reversing myeloid-derived suppressor cells mediated immunosuppression via p38α inhibition enhances immunotherapy efficacy in triple negative breast cancer
Abstract Infiltration of myeloid-derived suppressor cells (MDSCs) leads to Immunosuppressive tumor microenvironment (TME), which is one of the major causes for low objective response rates of immune checkpoint blockade (ICB) therapy. Here, we report that chemical inhibition of p38α reverses this MDSC-induced immunosuppressive TME and improves the immunotherapy efficacy in triple negative breast cancer (TNBC). Firstly, by combining the tumor immunological phenotype (TIP) gene signature and high throughput sequencing based high throughput screening (HTS2), we identified that ponatinib significantly inhibits the expression of “cold” tumor associated chemokines CXCL1 and CXCL2 in cancer cells. This inhibition decreases the infiltration of MDSCs and consequently increased the accumulation of “hot” tumor associated T cells and NK cells and thus reverses the immunosuppressive TME. Then, by multiple preclinical models, we found that ponatinib significantly inhibits tumor growth in a TME-dependent manner and enhances the efficacy of anti-PD-L1 immunotherapy on TNBC in vivo. Notably, ponatinib exhibits no significant inhibition on immune cells in mouse spleens. Mechanistically, ponatinib directly inhibits the kinase activity of p38α, which results in the reduction of the phosphorylation of STAT1 at Ser727, and thus the decreased expression of CXCL1 and CXCL2 in cancer cells. Our study provided the therapeutic potential of combining p38α inhibition with ICB for the treatment of TNBC.
Wang Dong、Dai Yifei、Yang Ming、Wang Haiyan、Wang Huili、Zhang Guanbin、Yu Xiankuo、Wang Yumei、Li Lu、Lin Kequan、Shao Wei、Wang Qianyu、Li Shasha
State Key Laboratory of Southwestern Chinese Medicine Resources, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine||Department of Basic Medical Sciences, School of Medicine, Tsinghua University||Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan UniversityDepartment of Basic Medical Sciences, School of Medicine, Tsinghua UniversityDepartment of Basic Medical Sciences, School of Medicine, Tsinghua UniversityDepartment of Basic Medical Sciences, School of Medicine, Tsinghua University||Department of Pathology, School of Medicine, Qinghai UniversityDepartment of Basic Medical Sciences, School of Medicine, Tsinghua UniversityDepartment of Laboratory Medicine, Fujian Medical University||Mianyang People?ˉs HospitalState Key Laboratory of Southwestern Chinese Medicine Resources, School of Basic Medical Sciences, Chengdu University of Traditional Chinese MedicineState Key Laboratory of Southwestern Chinese Medicine Resources, School of Basic Medical Sciences, Chengdu University of Traditional Chinese MedicineSchool of Life Sciences, Tsinghua UniversityState Key Laboratory of Southwestern Chinese Medicine Resources, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine||Department of Cardiology of The Second Affiliated Hospital, School of Medicine, Zhejiang University||Cardiovascular Key Laboratory of Zhejiang ProvinceDepartment of Basic Medical Sciences, School of Medicine, Tsinghua University||Iomics Biosciences IncState Key Laboratory of Southwestern Chinese Medicine Resources, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine||School of Life Sciences, Tsinghua UniversityDepartment of Basic Medical Sciences, School of Medicine, Tsinghua University||Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-Sen University
肿瘤学基础医学药学
PonatinibMDSCsp38αchemokinesimmunosuppressive tumor microenvironment
Wang Dong,Dai Yifei,Yang Ming,Wang Haiyan,Wang Huili,Zhang Guanbin,Yu Xiankuo,Wang Yumei,Li Lu,Lin Kequan,Shao Wei,Wang Qianyu,Li Shasha.Reversing myeloid-derived suppressor cells mediated immunosuppression via p38α inhibition enhances immunotherapy efficacy in triple negative breast cancer[EB/OL].(2025-03-28)[2025-05-11].https://www.biorxiv.org/content/10.1101/2023.03.31.535102.点此复制
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